The broad theme of research in this laboratory is to understand how physical activity influences growth and development in children and adolescents. The focus of the proposed studies is on delineating the mechanisms of a seeming paradox in the biological link between exercise and growth. Brief (5-week) periods of exercise training in children and adolescents improved muscle mass and cardiorespiratory function but led to reductions, rather than the expected increase, in circulating levels of insulin-like growth factor-I (IGF-I). This was surprising because physical activity is mechanistically linked, in part, to anabolic function through the growth hormone (GH)->IGF-I axis, and fitter adolescents and adults tend to have higher levels of IGF-I. It is hypothesized that exercise in children and adolescents leads to a catabolic environment, but simultaneously results in compensatory mechanisms that allow growth processes to continue. The catabolic environment likely arises from exercise stimulation of three inflammatory growth process to continue. The catabolic environment likely arises from exercise stimulation of three inflammatory cytokines [interleukin-1beta, -6, and tumor necrosis factor- alpha (IL-1beta, IL-6, and TNF-alpha)] which in turn inhibit the GH-IGF- I axis. The compensatory mechanisms include proteolysis of IGF binding protein-3, increased tissue IGF-I receptors, and adjustments of other IGF binding proteins. In a compensated catabolic state of exercise training (moderate intensity), the cytokine response eventually diminishes followed by a rebound in anabolic activity of the GH-IGF-I axis. By contrast, in an uncompensated catabolic state (e.g., when the exercise training is of very high intensity), cytokines remain elevated, the GH- IGF-1 axis stays suppressed, and growth is impaired. The first Specific Aim is to investigate acute growth factor and cytokine responses to brief bouts of exercise in male and female, children and adolescents. The Second Specific Aim is to determine the interactions between the cytokine and GH->IGF-I systems that occur when levels of physical activity are increased with a training program of moderate intensity over a six month period. School-based training programs are planned in which muscle mass will be assessed y magnetic resonance imaging, limb growth by knemometry, protein turnover by stable isotope methods, serum mitogenic activity by measurements of growth factors and cytokines and by in vitro cell culture responses, and tissue IGF-I receptor characteristics using erythrocytes. The Third Specific Aim is to perform similar studies in high school wrestlers (male and female), a sport known for its high intensity and tendency to develop a true catabolic state. This research will help determine the physiological mechanisms of growth versus growth plus exercise, a necessary step in defining levels of exercise that are beneficial for healthy children; for obese children, and for those with chronic disease disability.